Role of the αC-β4 loop in protein kinase structure and dynamics

Autor: Jian Wu, Nisha A Jonniya, Sophia P Hirakis, Cristina Olivieri, Gianluigi Veglia, Alexandr P Kornev, Susan S Taylor
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: eLife, Vol 12 (2024)
Druh dokumentu: article
ISSN: 2050-084X
DOI: 10.7554/eLife.91980
Popis: Although the αC-β4 loop is a stable feature of all protein kinases, the importance of this motif as a conserved element of secondary structure, as well as its links to the hydrophobic architecture of the kinase core, has been underappreciated. We first review the motif and then describe how it is linked to the hydrophobic spine architecture of the kinase core, which we first discovered using a computational tool, local spatial Pattern (LSP) alignment. Based on NMR predictions that a mutation in this motif abolishes the synergistic high-affinity binding of ATP and a pseudo substrate inhibitor, we used LSP to interrogate the F100A mutant. This comparison highlights the importance of the αC-β4 loop and key residues at the interface between the N- and C-lobes. In addition, we delved more deeply into the structure of the apo C-subunit, which lacks ATP. While apo C-subunit showed no significant changes in backbone dynamics of the αC-β4 loop, we found significant differences in the side chain dynamics of K105. The LSP analysis suggests disruption of communication between the N- and C-lobes in the F100A mutant, which would be consistent with the structural changes predicted by the NMR spectroscopy.
Databáze: Directory of Open Access Journals